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The mitochondrial genome in Wolfram syndrome
  1. * Department of Endocrinology, Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, UK
  2. Department of Paediatrics, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK
  3. Molecular Genetics Laboratory, The Churchill Hospital, Oxford OX3 7LJ, UK
  4. §Department of Neuropathology, The Medical School, University of Birmingham, Birmingham, UK
  1. Dr Barrett, T.G.Barrett{at}

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Editor—Wolfram syndrome is the association of juvenile onset diabetes mellitus and optic atrophy,1 also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). This is a progressive, neurodegenerative disorder, with diabetes mellitus and optic atrophy presenting in the first decade,2 cranial diabetes insipidus, and sensorineural deafness in the second, and neuropathic bladder in the third, followed by neurological complications (cerebellar ataxia, myoclonus) and psychiatric illness in the fourth decade. The clinical phenotype is consistent with an ATP supply defect, suggesting a mitochondrial mediated disease.3 Mitochondrial genome deletions and pathogenic point mutations4 5 have been described in Wolfram patients. A nuclear gene WFS1, wolframin,6 7 was recently identified, encoding a polypeptide of 890 amino acids. Wolfram syndrome thus appears to be genetically heterogeneous. Recently, a distinct “mitochondrial haplotype” was described.8 Because recombination does not appear to be characteristic of mtDNA, the accumulation of polymorphisms can be used as a “genetic clock” to estimate diversity within and between populations.9 A cluster of nucleotide exchanges at nucleotide positions 4216 and 11 251 roughly distinguished a series of 6/8 Wolfram patients from controls and patients with Leber hereditary optic neuropathy (LHON). The authors suggested that these mtDNA variants may predispose to Wolfram syndrome.8 We investigated our cohort of 50 Wolfram syndrome patients10 for evidence of a distinct mitochondrial haplotype and mitochondrial DNA rearrangements.

Patients for this study were included from a cohort recruited nationally in the UK.10 Minimal ascertainment criteria were juvenile onset (less than 30 years of age) diabetes mellitus and optic atrophy. These were chosen as the only features consistently present and earliest to develop in 166/168 case reports.11Diabetes mellitus was defined as a fasting plasma glucose of more than 6.0 mmol/l (>3 SD above the …

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